The long-term goal of this research is to elucidate molecular mechanisms underlying sensory perception. Specifically, we seek in this proposal to understand how Ca2+ feedback mechanisms regulate olfactory sensory neuron (OSN) function in vivo and how these mechanisms contribute to the ability of the animal to detect and discriminate odors. Ca2+ plays a central role in regulating OSN responses by modulating several signal transduction proteins via calmodulin (CaM). Previous in vitro studies have implicated the olfactory cyclic nucleotide-gated (CNG) channel and phosphodiesterase 1C (PDE1C) as major targets of Ca2+/CaM. However, the functional significance of these Ca2+/CaM-target interactions in OSN physiology and olfactory behavior has not been determined. We are employing molecular genetics to specifically eliminate Ca2+/CaM binding sites in the CNG channel and PDE1C. This approach allows a systematic analysis of the role of Ca2+/CaM in regulating OSN physiology, and ultimately olfactory behavior. In Specific Aim 1 we will determine the contribution of individual CaM-binding domains of the CNG channel to Ca2+/CaM regulation of OSN responses. Specific Aim 2 seeks to delineate how the basal activity and Ca2+/CaM-stimulated activity of PDE1C independently regulate OSN responses. In Specific Aim 3, we will investigate how regulation of OSN physiology aids olfactory behaviors such as odor tracking and discrimination. The proposed experiments will lead to a better understanding of the connection from regulation of signal transduction proteins to OSN physiology, and to olfactory behavior. This knowledge will further our understanding of normal olfactory function and olfactory dysfunctions, and will provide insight into principles common to all sensory systems. This research aims to understand how regulation of key proteins in the odor-detecting cells influences the sense of smell. The knowledge from these studies will add to our understanding of both the normal function of the olfactory system and olfactory dysfunctions.